Ellis is one of three players to have made it to the Major Leagues who played for the Rapid City Post 22 American Legion baseball program. As a 16-year-old, Ellis was the starting shortstop for the 1993 Rapid City Post 22 varsity "Hardhat" baseball team that touted a 70–5 record and won the national title in Roseburg, Oregon. In the back-to-back years (1994 & 1995), Ellis earned South DakotaAmerican Legion Player of the Year honors.[2]

He went on to play for the University of FloridaGators baseball program and was the MVP of the Gainesville regional at the 1998 College World Series. Although he has played his Major League career at second base, he was the starting third baseman at Florida, where that position was nicknamed "Ellis Island" due to Ellis' tremendous range and all-around fielding prowess.[citation needed]

Ellis made his Major League debut on April 9, 2002 for the Athletics against the Texas Rangers, pinch-running in the eighth inning for Jeremy Giambi. He remained in the game and ground out to short in the 10th inning.[4] He recorded his first base hit, in his first Major League start, on April 18 against the Anaheim Angels, a single to left field off of Ramón Ortiz.[5] His first home run was hit on June 28, 2002 off of San Francisco Giants pitcher Jay Witasick.[6] For the 2002 season, his batting was .272 in 98 games. Ellis hit .248 the following season, but missed the entire 2004 season due to a torn labrum in his right shoulder resulting from a collision with shortstop Bobby Crosby in a spring training game against the Chicago Cubs.[7] In 2005, he returned to the Athletics and led the team in batting average (.316), on-base percentage (.384), and slugging average (.477) as the team's regular second baseman.

On June 4, 2007, Ellis became only the sixth player in Oakland Athletics history to hit for the cycle. On July 23, 2007, he had his first career multi-home run game against the Los Angeles Angels of Anaheim. On August 5, 2007, he tied the A's team record for consecutive error-less games by a second baseman at 70 games.

Ellis missed the last two months of the 2008 season due to cartilage damage in his shoulder. He underwent successful surgery that also fixed a torn labrum from a previous injury.[10]

In October 2008, the Athletics signed Ellis to an $11 million contract through 2010, with an option of extending the deal an additional season.[11]

On June 30, 2011, Ellis was traded to the Colorado Rockies for Bruce Billings and a player to be named later.[12] On September 30, the Athletics announced that they received 22-year-old outfielder Eliezer Mesa to complete the deal.[13]

After a strong start, Ellis' leg was severely injured on May 20, 2012 by a hard slide from Tyler Greene of the St. Louis Cardinals while Ellis was attempting to turn a double play. Initially saying that he was okay, Ellis did not go to the hospital until the following day when he experienced extreme discomfort and swelling in his lower leg. After performing a fasciotomy to allow room within his leg for the swollen muscle tissue, his doctor later said that Ellis might have lost his leg if the surgery had been performed only six or seven hours later than it was.[15][16][17] Doctors said Ellis' injury was a rare one for athletes, but more common for victims of car accidents.[15][16] Ellis was expected to be out for six weeks and did not rejoin the Dodgers till July 4.

Overall he appeared in 110 games for the Dodgers in 2012, hitting .258 with 7 home runs and 31 RBI.

In the 2011 film, Moneyball, focusing on the Oakland A's analytical approach to economically assembling a competitive baseball team, the role of Mark Ellis is played by Brent Dohling, the baseball coach of Tarbut V' Torah.[20]